Circulating LDL that enters the blood vessel wall is the main source of cholesterol that accumulates within vessel wall atherosclerotic plaques, the cause of most heart attacks and strokes. Much of the deposited cholesterol accumulates within plaque macrophages converting these macrophages into cholesterol-rich foamy looking cells. Plaque macrophages are derived from circulating monocytes that enter the vessel wall and then differentiate into macrophages. Cholesterol accumulation in macrophages not only contributes to cholesterol retention within the vessel wall, but also alters macrophage biology. Cholesterol-loaded macrophages secrete plaque disrupting matrix metalloproteinase enzymes and produce tissue factor that promotes thrombosis when plaques rupture. Thus, how macrophages accumulate cholesterol and become foam cells has been the subject of intense investigation. It is generally believed that only LDL modified by oxidation, but not native (i.e., unmodified) LDL, can cause cholesterol accumulation in macrophages. However, most LDL within atherosclerotic plaques is not oxidized, and oxidized LDL is a poor inducer of macrophage cholesterol accumulation.[unreadable] In this research project, we have investigated how modification of macrophages rather than modification of LDL affects macrophage metabolism of native LDL. We have learned that macrophage cholesterol accumulation can occur with native LDL when macrophages are differentiated from monocytes with the specific growth factor, M-CSF. M-CSF differentiated macrophages show constitutive uptake and degradation of native LDL. LDL uptake does not depend on macrophage oxidation of LDL or macrophage binding of LDL. Rather, the M-CSF differentiated macrophages take up the LDL by constitutive macropinocytosis, a process by which macrophages and some other cell types take up large amounts of fluid. The macrophages take up LDL as part of the fluid that they ingest during macropinocytosis. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques. This novel mechanism of macrophage cholesterol accumulation shows that modification of LDL is not necessary for foam cell formation to occur. In addition, the findings direct attention to macrophage macropinocytosis as a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis.[unreadable] Liver X receptors (LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Several studies have recently shown that LXRs inhibit atherosclerosis development in animals. It is currently believed that the mechanism by which LXRs inhibit atherosclerosis is by promoting macrophage cholesterol efflux via induction of the genes encoding ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1) in macrophages. During the past year, we investigated whether LXRs affect macrophage uptake of LDL and cholesterol accumulation in human monocyte-derived macrophages. We learned that differentiation of macrophages in the presence of LXR agonists greatly decreases macrophage macropinocytosis of LDL and as a result decreases cholesterol accumulation. These findings reveal a novel mechanism by which LXR agonists may inhibit cholesterol accumulation and atherosclerosis, namely by inhibiting macrophage uptake of LDL. These new findings show that macropinocytosis of LDL is a process that can be regulated and targeted with drugs.